Spleen cells from mice of different inbred strains sharing the same H-2 haplotype but differing in their non-H-2 genetic background were compared for their ability to generate cytotoxic T lymphocyte (CTL) responses to syngeneic cells modified with the trinitrophenyl hapten (TNP-self). In both primary and secondary responses, high and low CTL strains were observed (i.e. non-H-2-linked Ir gene control). Among H-2(d) strains the BALB/c was a high responder strain, whereas DBA/2 and B10.D2 were low responder strains. Among H-2(k) mice, C3H, AKR/J and B10.BR were the respective high, intermediate, and low responders. Of the H-2(b) strains studied C57BL/6 were high, whereas C3H.SW and C57BL/10 were low responder strains to TNP-self. By using different combinations of responding, stimulating and target cells, it was found that these non-H-2-linked differences were not attributable to stimulating or target cells. These studies raise some interesting issues concerning the role of non-major histiocompatibility complex (MHC) genes in regulating CTL responses to foreign antigens recognized in association with self MHC gene products.